This study drew on the biological sensitivity to context model (Ellis & Boyce, 2008) and polyvagal theory (Porges, 2007) to evaluate the moderating influence of children's autonomic nervous system (ANS) regulation on pathways from child emotional abuse (CEA) and child physical abuse (CPA) to later dissociative symptoms in adolescence. Participants were 232 youth (50.2% assigned female at birth, 45.9% Latine) who reported on their experiences of CEA and CPA at ages 6, 8, and 10 years. Resting cardiography measures of respiratory sinus arrythmia (RSA) and pre-ejection period (PEP) assessed children's parasympathetic and sympathetic activation, respectively, at these same ages. Youth reported on their dissociative symptoms at age 17. Parasympathetic activation qualified predictions from CEA to dissociative symptoms with relatively high RSA sensitizing children to CEA effects. Sympathetic activation qualified interactive predictions from both CEA and CPA to dissociative symptoms, but in different directions depending on the level of CPA. These findings suggest that resting ANS regulation may sensitize children to the effects of CEA and/or CPA on later dissociative symptoms in adolescence.

Endophytic fungi are essential microorganisms in promoting plant health. However, the mechanism of endophytic fungi regulating root microbiota to enhance crop production and resistance remains unclear.

Postoperative activity restrictions can affect patient satisfaction after midurethral sling (MUS) surgery.

Fabry disease, a rare X-linked hereditary lysosomal storage disorder caused by mutations in the GLA gene, affecting multiple organs. However, functional validation data on the pathogenicity of novel mutations and research on the effects of migalastat intervention at different mutation sites is lacking.

Neuroinflammation is an inflammatory response in the central nervous system associated with various neurological conditions. The inflammatory process is typically treated with non-steroidal and steroidal anti-inflammatory drugs, which have a range of serious adverse effects. As an alternative, naturally derived molecules such as quercetin and its derivatives show promising anti-inflammatory properties and beneficial effects on various physiological functions. Our objective was to synthesize the evidence on the anti-inflammatory effect of quercetin and its derivatives in in vivo models, in the face of neuroinflammatory insults induced by lipopolysaccharide, through a systematic review and meta-analysis. A search of the preclinical literature was conducted across four databases (PubMed, Web of Science, Scielo, and Google Scholar). Studies were selected based on inclusion and exclusion criteria, assessed for methodological quality using CAMARADES, and risk of bias using the SYRCLE tool, and data were extracted from the studies. The quantitative assessment of quercetin effects on the expression of pro-inflammatory cytokines and microgliosis was performed through a meta-analysis. A total of 384 potentially relevant articles were identified, of which 11 studies were included in the analysis. The methodological quality was assessed, resulting in an average score of 5.8/10, and the overall risk of bias analysis revealed a lack of methodological clarity in most studies. Furthermore, through the meta-analysis, it was observed that treatment with quercetin statistically reduces pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin 6, interleukin 1β ( n = 89; SMD = -2.00; 95% CI: -3.29 to -0.71), and microgliosis ( n = 33; SMD = -2.56; 95% CI: -4.07 to -1.10). In terms of underlying mechanisms, quercetin and its derivatives exhibit antioxidant and anti-apoptotic properties, possibly through the nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathways, increasing the expression of antioxidant enzymes and reducing reactive species, and modulating the caspase pathway, increasing levels of anti-apoptotic proteins and decreasing pro-apoptotic proteins. Quercetin and its derivatives exhibit highly pleiotropic actions that simultaneously contribute to preventing neuroinflammation. However, despite promising results in animal models, future directions should focus on well-designed clinical studies to assess the safety, bioavailability, and efficacy of quercetin and its derivatives in humans. Additionally, standardization of methods and dosages in studies is crucial to ensure consistency of findings and optimize their application in clinical settings.

JOURNAL/nrgr/04.03/01300535-202604000-00043/figure1/v/2025-06-30T060627Z/r/image-tiff Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells, which is involved in retinal ganglion cell apoptosis in glaucoma. Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma. In this study, we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation. Following this, we treated Müller glial cells in vitro and in vivo with the mGluR I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr 9 Asp overexpression. We found that both Kir4.1 and Kir4.1 Tyr 9 Asp overexpression inhibited activation of Müller glial cells. Subsequently, we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr 9 Asp in the eye, and observed similar results in Müller cells in vivo as those seen in vitro . Both Kir4.1 and Kir4.1 Tyr 9 Asp overexpression inhibited Müller cell activation, regulated the balance of Bax/Bcl-2, and reduced the mRNA and protein levels of pro-inflammatory factors, including interleukin-1β and tumor necrosis factor-α. Furthermore, we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr 9 Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia. In this co-culture system, we observed elevated adenosine triphosphate concentrations in activated Müller cells, increased levels of translocator protein (a marker of microglial activation), and elevated interleukin-1β mRNA and protein levels in microglia induced by activated Müller cells. These changes could be reversed by Kir4.1 and Kir4.1 Tyr 9 Asp overexpression in Müller cells. Kir4.1 overexpression, but not Kir4.1 Tyr 9 Asp overexpression, reduced the number of proliferative and migratory microglia induced by activated Müller cells. Collectively, these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma. Kir4.1 and Kir4.1 Tyr 9 Asp overexpression attenuated Müller cell activation, reduced ATP/P2X receptor-mediated interactions between glial cells, inhibited microglial activation, and decreased the synthesis and release of pro-inflammatory factors, consequently ameliorating retinal ganglion cell apoptosis in glaucoma.

This study investigated the use of group body mapping as a methodological tool to explore experiences of obstetric violence among migrant women from Senegal, Morocco, and Pakistan in Catalonia. The research aimed to assess the effectiveness of group body mapping in identifying the barriers these women faced during pregnancy, childbirth, and the postpartum period, while also highlighting the intersectional dimensions of obstetric violence. The study identified seven key codes-Issues/Barriers, Trust, Gender, Body/Embodiment, Significant Relationships, Employment, and Gender-Based Violence-which were analyzed from an intersectional perspective. Group body mapping was presented as an effective strategy to visualize structural and invisible barriers, offering a deeper understanding of the sociocultural dynamics that affected migrant women's access to and experience of sexual and reproductive health services. This technique complemented traditional research methods by capturing complex narratives and revealing systemic structures tied to social status, gender, religion, language, and age. It empowered women to reclaim agency over their experiences within historically medicalized and colonized healthcare systems. Ultimately, the research highlighted the transformative potential of group body mapping in advancing healthcare equity and promoting culturally and gender-sensitive sexual and reproductive health services for marginalized populations.

The impact of non-antibiotic feed additives on livestock performance and health is contingent upon a multitude of variables, including the animal species, dosage and type of feed additives, and duration of oral administration. However, there is a paucity of knowledge regarding the relationship between these factors and the performance of livestock animals.

Previous work suggests that the gut microbiome can be disrupted by antibiotics, anesthetics, opiates, supplemental oxygen, or nutritional deprivation-all of which are common and potentially modifiable perioperative interventions that nearly all patients are exposed to in the setting of surgery. Gut microbial dysbiosis has been postulated to be a risk factor for poor surgical outcomes, but how perioperative care-independent of the surgical intervention-impacts the gut microbiome, and the potential consequences of this impact have not been directly investigated.

Direct anticoagulants inhibit coagulation serine proteases by reversibly engaging their active site with high affinity. By modifying the S4 active site subpocket of factor (F)Xa, we introduced inhibitor resistance while preserving catalytic activity. Given the homology between FXa and thrombin in active site architecture and direct anticoagulant binding, we have targeted the S4 subsite to introduce inhibitor resistance in (pro)thrombin.Recombinant prothrombin variants were generated in which I174 was substituted or sequence R92-N98 was exchanged with that of human kallikrein-3.Specific prothrombin clotting activity of the variants was 6-fold (intrinsic clotting) to 10-fold (extrinsic clotting) reduced relative to wild-type prothrombin. Further analyses revealed that modification of the S4 subsite hampers fibrinogen and thrombomodulin-mediated protein C conversion by thrombin. Consistent with this, the thrombin variants displayed a reduced catalytic efficiency toward the peptidyl substrate used in thrombin generation assessments. The variants displayed a 2-fold reduced sensitivity for dabigatran relative to wild-type prothrombin, while argatroban inhibition was unaffected. Analyses using a purified component system revealed an up to 24-fold and 4-fold reduced IC50 for inhibition of thrombin by dabigatran and argatroban, respectively. Molecular dynamics (MD) simulations of both dabigatran-bound and unbound (apo) modified thrombin variants indicated these to comprise a larger inhibitor binding pocket relative to wild-type thrombin and display reduced inhibitor binding. As a net effect, (pro)thrombin variants with S4 subsite modifications supported detectable fibrin formation at therapeutic dabigatran concentrations.Our findings provide proof-of-concept for the engineering of thrombin variants that are resistant to direct thrombin inhibitors by modulating the S4 subsite.

The vicarious cognitive dissonance process predicts that observing an inconsistent act by a member of the ingroup causes uncomfortable arousal in the observer, inducing a motivation to reduce this discomfort. This meta-analysis examined the effect of vicarious cognitive dissonance based on 24 studies (N = 16,769). Our results indicated a small effect for the vicarious cognitive dissonance (g = 0.41 [0.27, 0.54], p <.001) with important variability between the outcomes. Our moderator analysis was limited by the low number of included studies. Publication bias analyses indicate a small true effect size (e.g., 3PSM: g = 0.22, p = .042), that was inflated by small sample sizes (R-index = 14.6%). We discussed theoretical issues concerning the psychological processes underlying vicarious cognitive dissonance, and methodological questions concerning operationalization. We proposed ways of improving the design and procedure to ensure that the effects found in the literature exist and are replicable.

JOURNAL/nrgr/04.03/01300535-202605000-00039/figure1/v/2025-10-21T121913Z/r/image-tiff Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells. However, adult tissue-derived mesenchymal stem cells encounter various obstacles, including limited tissue sources, invasive acquisition methods, cellular heterogeneity, purification challenges, cellular senescence, and diminished pluripotency and proliferation over successive passages. In this study, we used induced pluripotent stem cell-derived mesenchymal stem cells, known for their self-renewal capacity, multilineage differentiation potential, and immunomodulatory characteristics. We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury. Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation. Furthermore, the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats. Additionally, our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization. Collectively, our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats, offering promising therapeutic strategies for clinical translation.

JOURNAL/nrgr/04.03/01300535-202604000-00038/figure1/v/2025-06-30T060627Z/r/image-tiff Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage. However, during minimally invasive surgery, recombinant tissue plasminogen activator may come into contact with brain tissue. Therefore, a thorough assessment of its safety is required. In this study, we established a mouse model of intracerebral hemorrhage induced by type VII collagenase. We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage, reduced pathological damage, and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma. In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin, the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis, autophagy, and endoplasmic reticulum stress. Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons. Moreover, the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis, autophagy, and endoplasmic reticulum stress. Furthermore, to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects, various inhibitors were used to target distinct domains. It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway. These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage, possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.

JOURNAL/nrgr/04.03/01300535-202601000-00039/figure1/v/2025-06-09T151831Z/r/image-tiff The NSC-34 cell line is a widely recognized motor neuron model and various neuronal differentiation protocols have been exploited. Under previously reported experimental conditions, only part of the cells resemble differentiated neurons; however, they do not exhibit extensive and time-prolonged neuritogenesis, and maintain their duplication capacity in culture. The aim of the present work was to facilitate long-term and more homogeneous neuronal differentiation in motor neuron-like NSC-34 cells. We found that the antimitotic drug cytosine arabinoside promoted robust and persistent neuronal differentiation in the entire cell population. Long and interconnecting neuronal processes with abundant growth cones were homogeneously induced and were durable for up to at least 6 weeks in culture. Moreover, cytosine arabinoside was permissive, dispensable, and mostly irreversible in priming NSC-34 cells for neurite initiation and regeneration after mechanical dislodgement. Finally, the expression of the cell proliferation antigen Ki67 was inhibited by cytosine arabinoside, whereas the expression levels of neuronal growth associated protein 43, vimentin, and motor neuron-specific p75, Islet2, homeobox 9 markers were upregulated, as confirmed by western blot and/or confocal immunofluorescence analysis. Overall, these findings support the use of NSC-34 cells as a motor neuron model for properly investigating neurodegenerative mechanisms and prospectively identifying neuroprotective strategies.

JOURNAL/nrgr/04.03/01300535-202604000-00041/figure1/v/2025-06-30T060627Z/r/image-tiff Contrary to the adult central nervous system, the peripheral nervous system has an intrinsic ability to regenerate that relies on the expression of regeneration-associated genes, such as some kinesin family members. Kinesins contribute to nerve regeneration through the transport of specific cargo, such as proteins and membrane components, from the cell body towards the axon periphery. We show here that KIF4A, associated with neurodevelopmental disorders and previously believed to be only expressed during development, is also expressed in the adult vertebrate nervous system and up-regulated in injured peripheral nervous system cells. KIF4A is detected both in the cell bodies and regrowing axons of injured neurons, consistent with its function as an axonal transporter of cargoes such as β1-integrin and L1CAM. Our study further demonstrates that KIF4A levels are greatly increased in Schwann cells from injured distal nerve stumps, particularly at a time when they are reprogrammed into an essential proliferative repair phenotype. Moreover, Kif4a mRNA levels were approximately ~ 6-fold higher in proliferative cultured Schwann cells compared with non-proliferative ones. A hypothesized function for Kif4a in Schwann cell proliferation was further confirmed by Kif4a knockdown, as this significantly reduced Schwann cell proliferation in vitro . Our findings show that KIF4A is expressed in adult vertebrate nervous systems and is up-regulated following peripheral injury. The timing of KIF4A up-regulation, its location during regeneration, and its proliferative role, all suggest a dual role for this protein in neuroregeneration that is worth exploring in the future.

JOURNAL/nrgr/04.03/01300535-202603000-00038/figure1/v/2025-06-16T082406Z/r/image-tiff The dentate gyrus of the hippocampus is a plastic structure that displays modifications at different levels in response to positive stimuli as well as to negative conditions such as brain damage. The latter involves global alterations, making understanding plastic responses triggered by local damage difficult. One key feature of the dentate gyrus is that it contains a well-defined neurogenic niche, the subgranular zone, and beyond neurogenesis, newly born granule cells may maintain a "young" phenotype throughout life, adding to the plastic nature of the structure. Here, we present a novel experimental model of local brain damage in organotypic entorhino-hippocampal cultures that results in the activation of adjacent newly born granule cells. A small piece of filter paper was placed on the surface of the granule cell layer of the dentate gyrus, which evoked a foreign body reaction of astrocytes, along with the activation of local young neurons expressing doublecortin. Forty-eight hours after foreign body placement, the number of doublecortin-immunoreactive cells increased in the subgranular zone in the direct vicinity of the foreign body, whereas overall increased doublecortin immunoreactivity was observed in the granule cell layer and molecular layer of the dentate gyrus. Foreign body placement in the pyramidal layer of the CA1 region evoked a comparable local astroglial reaction but did not lead to an increase in doublecortin-immunoreactive in either the CA1 region or the adjacent dentate gyrus. Seven days after foreign body placement in the dentate gyrus, the increase in doublecortin-immunoreactivity was no longer observed, indicating the transient activation of young cells. However, 7 days after foreign body placement, the number of doublecortin-immunoreactive granule cells coimmunoreactive for calbindin was lower than that under the control conditions. As calbindin is a marker for mature granule cells, this result suggests that activated young cells remain at a more immature stage following foreign body placement. Live imaging of retrovirally green fluorescent protein-labeled newly born granule cells revealed the orientation and growth of their dendrites toward the foreign body placement. This novel experimental model of foreign body placement in organotypic entorhino-hippocampal cultures could serve as a valuable tool for studying both glial reactivity and neuronal plasticity, specifically of newly born neurons under controlled in vitro conditions.

Obesity presents a significant global health burden, necessitating insights into the molecular drivers of adipogenesis and adipose tissue regulation.

Topical application of l-menthol, a pharmacological cold-mimetic and agonist of the cold-sensing receptor TRPM8 (transient receptor potential cation channel subfamily M member 8), has been shown to stimulate brown adipose tissue (BAT) thermogenesis and reduce weight gain in both obese and lean male mice, without affecting energy intake. While these findings suggest that l-menthol could offer a novel approach to prevent weight gain, its potential to enhance the benefits of exercise on whole-body metabolic health remains unexplored. In this study, we investigated whether daily topical l-menthol application, combined with voluntary wheel running, could enhance exercise-induced improvements in metabolic health in male and female C57BL/6J mice housed at thermoneutrality (29°C). Our results demonstrated that although l-menthol treatment reduced voluntary wheel running distance, there was still a main effect of exercise to reduce fat mass, weight gain and improve glucose tolerance. Indirect calorimetry revealed that l-menthol increased total energy expenditure, potentially explaining improvements in metabolic health despite reductions in voluntary wheel running. These findings suggest that although l-menthol does not enhance the effects of voluntary exercise, it remains a promising strategy for improving metabolic health.

JOURNAL/nrgr/04.03/01300535-202603000-00044/figure1/v/2025-06-16T082406Z/r/image-tiff Parkinson's disease is characterized by synucleinopathy-associated neurodegeneration. Previous studies have shown that glucagon-like peptide-1 (GLP-1) has beneficial effects in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, the effect of GLP-1 on intrinsic synuclein malfunction remains unclear. In this study, we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in SncaA53T transgenic mice and explored the underlying mechanisms. Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death, reduced pathological aggregation of α-synuclein, and decreased movement disorders in SncaA53T transgenic mice. Furthermore, Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation, reduced cerebral activation of microglia and astrocytes, and promoted cell survival via the GLP-1 receptor/PI3K/Akt pathway in the substantia nigra. Additionally, Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammatory molecules including lipopolysaccharide, lipopolysaccharide binding protein, interleukin-1β, and interleukin-6. Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reversing gut dysbiosis in SncaA53T transgenic mice. Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in SncaA53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis. Collectively, our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson's disease.

WDR91, a WD40 repeat domain-containing protein, is a key regulator of endosomal trafficking, lysosomal function, and autophagy. It acts as a Rab7 effector, forming a complex with WDR81 to modulate phosphatidylinositol 3-kinase (PI3K) activity, endosomal maturation, and lysosome homeostasis. Loss-of-function variants in WDR91 are considered related to endosomal accumulation, impaired cargo degradation, and neurodegeneration. In this report, an autosomal recessive neurodevelopmental disorder is proposed, associated with WDR91 loss-of-function in a consanguineous family. The patient presented with severe microcephaly, dysmorphic features, and organomegaly, along with early onset psychomotor delay, hypotonia, sensorineural hearing impairment, and visual impairment. Whole-exome sequencing (WES) identified a homozygous splice site variant, NM_014149.4:c.1395+1G>A, predicted to disrupt the donor site and classified as likely pathogenic (PVS1, PM2). The variant was absent from population databases and our internal in-house cohort. Functional analysis supports a pathogenic role for the variant. WDR91 deficiency results in neuronal loss, cortical thinning, and impaired brain development, as evidenced in Wdr91 knockout models. Our study expands the clinical and genetic spectrum of WDR91-related disorders and highlights the need for further investigations to elucidate the precise molecular mechanisms underlying WDR91-associated pathogenesis.